The primary goal of cancer treatment is treatment and eradication of the growth of the primary tumor. Concurrent with this treatment it is necessary to prevent metastasis, which can be defined as separation of primary tumor cells and their subsequent penetration into the lymphatic system or blood vessels for dissemination. Such dissemination may occur by adhesion to and subsequent penetration through the endothelial walls, establishment of secondary tumors in the perivascular tissues and eventual spread of the tumor cells to more distant sites. Although much is known about the clinical manifestations of the metastatic process, little is understood about the biochemical, immunologic, genetic, and hormonal mechanisms involved in metastasis. Thus metastasis can be considered as a single phenomenom represented by an intricate series of events.
Because of the importance of both treatment of primary tumor growth and prevention of metastasis, cancer researchers have undertaken extensive research to define the interactions involved in tumor growth and metastasis.
One of the biological properties which tumor cells appear to possess is the ability to interact with and to attach to host blood platelets, enhancing the potential of the tumor to lodge in the microvasculature and adhere to vascular endothelium. Alternatively, it has been suggested that following lodging of the tumor cells, the cells may initiate the formation of surrounding protective platelet thrombi. For successful metastasis to occur, the metastatic cells must first lodge and adhere to the vascular endothelium and remain intravascular until it infiltrates into the surrounding tissue.
Because of the similarities of the process involved in the lodging and adherance of the tumor cells to the endothelium and the formation of non-tumor thrombi, many investigators have concluded that platelets are involved in some fashion. Because of this platelet involvement, numerous investigations have been undertaken to determine the effect of anticoagulant therapy on metastasis. The investigations referred to below involved the administration of anticoagulant compounds which are potent inhibitors of platelet aggregation. The results to date have been ambivalent.
Heparin has been reported to both decrease and increase metastasis, especially pulmonary. [See Cell Biol. Intl. Rep. 2: 81-86 (1963) and Arch. Surg. 91: 625-629 (1965)]. Aspirin has produced mixed results [See Eur. J. Cancer 8: 347-352 (1972) and Intl. J. Cancer 11: 704-718 (1973)]. Warfarin has been demonstrated to produce significant antimetastatic effects after intervenous injection of tumor cells and in spontaneously metastasizing tumors [See Cancer 35: 5-14 (1975) and Cancer Res 37: 272-277 (1971)]. It has been shown that metastasis induced by intravenous administration of B-16.sub.a melanoma cells can be prevented by administration of the anticoagulant agent prostacyclin [See Cell Biol. 87: 649 (1980)].
For a review of the use of anticoagulants in tumor therapy, see M. B. Donati, et al., Malignancy and the Hemostatic System, pp. 103-120, Raven Press, 1981.
It has been suggested that the use of anticoagulant therapy has been less than satisfactory in part because of the lack of specificity of the anticoagulant agents used and the fact that some of the agents produce effects on the tumor cells themselves which may overall, negate the desired effect on blood platelets, and hence metastasis.
According to the present invention, the compound 3-methyl-1-[2-(2-naphthyloxy)-ethyl]-2-pyrazolin-5-one, disclosed and claimed as a therapeutically efficacious antithrombotic agent in U.S. Pat. No. 4,053,621, has been found to be a potent antimetastatic agent without treating the tumor per se.